Metronidazole esters for treating rosacea

ABSTRACT

A compound of formula (I): 
     
       
         
         
             
             
         
       
     
     is described, as well as enantiomers, pharmaceutically acceptable salts thereof, and uses thereof.

The present invention relates to a compound of formula (I), and to itsuses as a medicament, especially in the treatment and/or prevention ofrosacea and in the treatment and/or prevention of inflammatorypathologies.

Rosacea is a progressive chronic common inflammatory dermatosisassociated with vascular relaxation. It mainly affects the central partof the face and is characterized by reddening of the face or hotflushes, facial erythema, papules, pustules, telangiectasia andoccasionally ocular lesions known as ocular rosacea. In serious cases,especially in men, the soft tissue of the nose may swell and produce abulbous swelling known as rhinophyma. Rosacea develops over severalyears via episodes that are worsened by various stimuli such astemperature variations, alcohol, spices, exposure to sunlight, oremotions.

Rosacea is classified into four subtypes as a function of variousclinical characteristics (Wilkin J. et al., JAAD, 2002, 46: 584-587).

The primary characteristics (histamine flushes, persistent erythema,papules and pustules, and telangiectasia) and secondary characteristics(burning or stinging sensation, plaques, dry appearance of the skin,oedema, ocular manifestations, phymatous changes) of rosacea are oftenobserved in combination. The most common modes of exteriorization orcombinations of signs are temporarily regrouped into specific subtypes,which are described below. Each category comprises the minimum number ofsigns that are sufficient to make a diagnosis of the correspondingsubtype (although the modes of exteriorization are not necessarilylimited to these signs), and it is possible that patients simultaneouslypresent characteristics suggesting more than one subtype of rosacea.

Subtype 1: Erythematotelangiectasic Rosacea

Erythematotelangiectasic rosacea is characterized mainly by histamineflushes and persistent central facial erythema. The presence oftelangiectasias is common, but not essential to the diagnosis of thissubtype. A central facial oedema, burning and stinging sensations, andredness or desquamation are also occasionally observed. History ofhistamine flushes alone are common in the case of patients sufferingfrom erythematotelangiectasic rosacea.

Subtype 2: Papulopustular Rosacea

Papulopustular rosacea is characterized by persistent central facialerythema and by transient papules and/or pustules distributed in thecentre of the face. However, the papules and pustules may also affectthe peri-orificial regions (i.e. the perioral, perinasal or periocularareas). The papulopustular subtype resembles common acne, but comedonesare absent. Rosacea and acne may coexist, and, besides the papules andpustules resembling rosacea, the patients concerned will also possiblyhave comedones. Patients suffering from papulopustular rosaceaoccasionally complain of burning and stinging sensations.

This subtype is often observed before or at the same time as subtype 1(including the presence of telangiectasias). The telangiectasias riskbeing masked by the persistent erythema and the papules or pustules.

Subtype 3: Phymatous Rosacea

Phymatous rosacea is manifested by thickening of the skin, nodules withan irregular surface and tumefaction. Rhinophyma is the commonestpresentation, but phymatous rosacea may affect other regions, includingthe chin, the forehead, the cheeks and the ears. In the case of patientssuffering from this subtype, the presence of enlarged and prominentfollicular apertures is occasionally reported in the affected region, asare telangiectasias.

This subtype is often observed before or at the same time as subtype 1or 2 (including the presence of persistent erythema, telangiectasias,papules and pustules). In the case of rhinophyma, these additionalstigmata risk being particularly pronounced in the nasal region.

Subtype 4: Ocular Rosacea (or Ophthalmic Rosacea)

The diagnosis of ocular rosacea must be envisaged when a patient has oneor more of the following ocular signs and symptoms: teary or bloodshotappearance (interpalpebral conjunctival hyperaemia), sensation ofpresence of a foreign body, of burning or stinging, dryness, itching,photosensitivity, blurred vision, telangiectasias of the conjunctiva andof the edge of the eyelid, or erythema of the eyelid and periocularerythema. Blepharitis, conjunctivitis and irregularity of the edges ofthe eyelid are other signs that may be detected. A chalazion or achronic staphylococcic infection manifested by a stye and whose cause isa dysfunction of the meibomian glands is a frequent sign of ocularaffection related to rosacea. Some patients complain of a reduction invisual acuity, which is due to corneal complications (punctuatekeratitis, corneal infiltrates/corneal ulcers or marginal keratitis). Byitself, the treatment of cutaneous rosacea may be without effect on therisk of lowering the visual acuity associated with ocular rosacea, andan ophthalmological approach will possibly be required.

Finally, other rarer forms of rosacea exist (variants), in particulargranulomatous rosacea.

The diagnosis of ocular rosacea is most often made when cutaneous signsand symptoms are also detected. However, it is not necessary forcutaneous signs and symptoms to be present in order to make thediagnosis, and small-scale studies suggest that up to 20% of patientssuffering from ocular rosacea may develop ocular signs and symptomsbefore cutaneous manifestations appear. Cutaneous lesions are the firstto appear in the case of about half of these patients, andmanifestations of the two types occur simultaneously in a minority ofthem.

Rosacea generally occurs between the ages of 25 and 70, and is much morecommon in people with fair complexion. It more particularly affectswomen, although this complaint is generally more severe in the case ofmen.

The pathogenesis of rosacea is poorly understood, and may involveseveral factors. These are, for example, vascular factors (abnormalvascular reactivity), immune factors, or alternatively exogenous factorssuch as the presence of follicular microorganisms such as bacteria andDemodex folliculorum mites (Diamantis S. & Waldorf H. A., J. DrugDermatol., 2006, 5: 8-12; Wilkin J. K., Arch. Dermatol., 1994, 130:359-362; Buechner S. A., Dermatology, 2005, 210: 100-108).

Moreover, studies, especially clinical studies, tend to suggest thatrosacea is an inflammatory pathology (McKeage et al., Am. J. Clin.Dermatol. 2010; 11(3): 217-22).

Conventionally, rosacea is treated orally or topically. Among the agentshaving a marketing authorization for the “rosacea” indication aretopical metronidazole and oral doxycycline (Cribier B., La rosacée,Masson-Eticom, Paris, 2002).

Long-term oral treatments with tetracycline derivatives are problematicfor many reasons, in particular on account of their significant sideeffects. The oral administration of tetracyclines, especiallydoxycycline, may induce photosensitivity, or even phototoxicity at andabove 100 mg/day (Layton A. M., Cunliffe W. J. Phototoxic eruptions dueto doxycycline-a dose-related phenomenon. Clin. Exp. Dermatol. 1993;18:425-427), or alternatively gastrointestinal disorders (Maibach H.Second-generation tetracyclines, a dermatologic overview: clinical usesand pharmacology. Cutis. 1991; 48:411-417).

In addition, these treatments do not make it possible to effectivelytreat and/or prevent all of the symptoms associated with rosacea.Considering the chronic nature of rosacea, with a typical profile ofremission and exacerbation, an ideal treatment requires use that may beprolonged, in a safe and effective manner.

Patent application WO 02/74290 describes the use of at least onenon-steroidal anti-inflammatory drug (NSAID) for treating rosacea. Thiscompound may especially be piroxicam, aspirin, ibufenac or naproxen. Itmay optionally be used in combination with a nitroimidazole. Thesimultaneous use of an NSAID and of a nitroimidazole has, however,appreciable side effects, especially gastrointestinal and renal effectsassociated with the use of metronidazole as nitroimidazole (D. I.Edwards, Br. J. Vener. Dis. 1980; 56: 285-290), or ulcers associatedwith the use of an NSAID (C. J. Hawkey, J. Rheumatology, 2002; 29: 4;650-652).

There is thus a need for active agents that are effective for treatingrosacea, which can be used for long periods, and which have the leastpossible side effects.

The aim of the present invention is thus to propose an effectivetreatment for rosacea, which especially reduces the side effects for thepatient. Preferably, this treatment is performed topically, whichconsiderably reduces any systemic side effect.

One subject of the present invention is thus a compound chosen from thecompound of formula (I) below:

enantiomers thereof and pharmaceutically acceptable salts thereof.

The compound of formula (I) has the chemical name2-(2-methyl-5-nitroimidazol-1-yl)ethyl2-(2-fluorobiphenyl-4-yl)propionate.

This compound contains an ester function, which is specifically cleavedin keratinocytes, as is demonstrated in Example 2. For comparativepurposes, other metronidazole esters with NSAIDs, for instanceindomethacin, niflumic acid, diflunisal or ketorolac esters, wereprepared and tested on keratinocyte cultures. All these compounds arestable in the presence of keratinocytes, unlike the compound of formula(I) according to the invention. This particular instability of thecompound of formula (I), enantiomers thereof and pharmaceuticallyacceptable salts thereof is thus surprising and unexpected. Withoutwishing to be bound by any theory, it is quite likely that thisparticular surprising instability of the compound of formula (I),enantiomers thereof and pharmaceutically acceptable salts thereof makesit possible to obtain the anti-inflammatory activity and theanti-rosacea activity once the compound of formula (I), enantiomersthereof or pharmaceutically acceptable salts thereof has (have)penetrated the skin and become hydrolysed on contact with thekeratinocytes.

Effectively, the hydrolysis on contact with keratinocytes of thecompound of formula (I), enantiomers thereof or pharmaceuticallyacceptable salts thereof releases metronidazole and flurbiprofen asindicated in Example 2.

However, surprisingly, the amount of metronidazole and flurbiprofendetected in the plasma, after topical application, is smaller when anamount of the compound of formula (I), an enantiomer thereof or apharmaceutically acceptable salt thereof is applied compared with whenthe same amount of an equimolar mixture of metronidazole andflurbiprofen is applied.

By way of example, the application to rat skin of a compositioncontaining 1.4% 2-(2-methyl-5-nitroimidazol-1-yl)ethyl(S)-2-(2-fluorobiphenyl-4-yl)propionate makes it possible to detectabout 2.3 times less metronidazole and about 6.7 times less flurbiprofenin the plasma when compared with application under the same conditionsof an equimolar mixture of metronidazole and flurbiprofen. The areasunder the curve representing the plasmatic concentration as a functionof time are used as an indication of the plasmatic exposure.

This particular and unexpected property of the compound of formula (I),enantiomers thereof or pharmaceutically acceptable salts thereof thusmakes it possible to minimize the plasmatic amounts of metronidazole andflurbiprofen, and thus to minimize the adverse side effects associatedwith these products, while at the same time maintaining usefulanti-inflammatory activity in the treatment of rosacea.

By way of example, the (S) and (R) enantiomers corresponding to thegeneral formula (I), namely, respectively,2-(2-methyl-5-nitroimidazol-1-yl)ethyl(S)-2-(2-fluorobiphenyl-4-yl)propionate and2-(2-methyl-5-nitroimidazol-1-yl)ethyl(R)-2-(2-fluorobiphenyl-4-yl)propionate, evaluated at a concentration of1% in the TPA test in mice as indicated in Example 3, show inhibition,respectively, of 95% and 85% for the TPA-induced inflammation. Forcomparative purposes, (S)-flurbiprofen and (R)-flurbiprofen showinhibition, respectively, of 70% and 80% when they are tested at thesame 1% concentration.

Thus, the compound of formula (I), enantiomers thereof orpharmaceutically acceptable salts thereof have anti-inflammatoryactivity that is useful in the treatment of rosacea while at the sametime being able to reduce the plasmatic concentration of metronidazoleand flurbiprofen when compared with the topical application of anequivalent concentration of an equimolar mixture of metronidazole andflurbiprofen.

The present invention also relates to a compound chosen from thecompound of formula (I), enantiomers thereof and pharmaceuticallyacceptable salts thereof, for its use as a medicament.

A subject of the present invention is also a compound chosen from thecompound of formula (I), enantiomers thereof and pharmaceuticallyacceptable salts thereof, for its use in the treatment and/or preventionof rosacea.

A subject of the present invention is also a compound chosen from thecompound of formula (I), enantiomers thereof and pharmaceuticallyacceptable salts thereof, for its use in the prevention and/or treatmentof inflammatory pathologies.

A subject of the present invention is also the use of at least onecompound chosen from the compound of formula (I), enantiomers thereofand pharmaceutically acceptable salts thereof, for preparing amedicament for treating and/or preventing rosacea.

A subject of the present invention is also the use of at least onecompound chosen from the compound of formula (I), enantiomers thereofand pharmaceutically acceptable salts thereof, for preparing amedicament for treating and/or preventing inflammatory pathologies.

The term “salts of the compound of formula (I) according to theinvention or salts of enantiomers thereof” means salts of this compoundor of enantiomers thereof with a pharmaceutically acceptable acid.

The pharmaceutically acceptable acid is especially:

-   -   a pharmaceutically acceptable inorganic acid, for instance        hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid        or hydrobromic acid;    -   or a pharmaceutically acceptable organic acid, for instance        acetic acid, tartaric acid, maleic acid, hydroxymaleic acid,        fumaric acid, citric acid, lactic acid, mucic acid, gluconic        acid, benzoic acid, succinic acid, oxalic acid, phenylacetic        acid, methanesulfonic acid, toluenesulfonic acid,        benzenesulfonic acid, salicylic acid, aspartic acid, glutamic        acid and ascorbic acid.

Preferably, the salts of the compound of formula (I) are chosen from thehydrochloride, the citrate, the salicylate and the benzoate of thecompound of formula (I).

The carbon atom located between the benzene ring and the —COO— group isasymmetric; the molecule is thus chiral. Thus, the term “enantiomers ofthe compound of formula (I)” means the R and S enantiomers of thiscompound. The S enantiomer is the preferred form.

Thus, the compound according to the invention is preferably2-(2-methyl-5-nitroimidazol-1-yl)ethyl(S)-2-(2-fluorobiphenyl-4-yl)propionate.

Preferably, the salts of the S enantiomer of the compound of formula (I)are chosen from the hydrochloride, the citrate, the salicylate and thebenzoate of the said S enantiomer (i.e.2-(2-methyl-5-nitroimidazol-1-yl)ethyl(S)-2-(2-fluorobiphenyl-4-yl)propionate hydrochloride,2-(2-methyl-5-nitroimidazol-1-yl)ethyl(S)-2-(2-fluorobiphenyl-4-yl)propionate citrate,2-(2-methyl-5-nitroimidazol-1-yl)ethyl(S)-2-(2-fluorobiphenyl-4-yl)propionate salicylate and2-(2-methyl-5-nitroimidazol-1-yl)ethyl(S)-2-(2-fluorobiphenyl-4-yl)propionate benzoate.

The term “treatment” or “treating” rosacea (or inflammatory pathologies)means reducing and/or inhibiting the development of rosacea (or ofinflammatory pathologies) and/or of the symptoms thereof.

The term “prevention” or “preventing” rosacea (or inflammatorypathologies) means reducing and/or avoiding the appearance of thesymptoms of rosacea (or of inflammatory pathologies).

The term “inflammatory pathologies” especially means cutaneousinflammatory pathologies, such as psoriasis, atopic dermatitis, acne oreczema.

The term “compound according to the invention” means, indiscriminantly,the compound of formula (I), an enantiomer thereof and/or apharmaceutically acceptable salt thereof.

More preferentially, the compound according to the invention is the Senantiomer of the compound of formula (I) or2-(2-methyl-5-nitroimidazol-1-yl)ethyl(S)-2-(2-fluorobiphenyl-4-yl)propionate of structure corresponding toformula (Ia)

The compound according to the invention may be prepared according to theprocess given in Example 1.

The compound chosen from the compound of formula (I), enantiomersthereof and pharmaceutically acceptable salts thereof may thus beformulated in pharmaceutical compositions for human use. The saidcompositions comprise, in a pharmaceutically acceptable medium, at leastone compound chosen from the compound of formula (I), enantiomersthereof and pharmaceutically acceptable salts thereof.

The term “pharmaceutically acceptable medium” means a medium that iscompatible with the skin, mucous membranes and the integuments.

The pharmaceutical composition that may be used according to theinvention may be administered topically, parenterally or orally.

Preferably, the compound chosen from the compound of formula (I),enantiomers thereof and pharmaceutically acceptable salts thereof ispresent in a pharmaceutical composition for topical application.

The term “topical application” means application to the skin, mucousmembranes and/or the integuments.

The composition according to the invention comprises from 0.001% to 10%by weight of compound(s) according to the invention relative to thetotal weight of the composition. Preferentially, the compositionaccording to the invention contains from 0.1% to 5% by weight ofcompound(s) according to the invention relative to the total weight ofthe composition.

The topical pharmaceutical composition may be in liquid, pasty or solidform, and more particularly in the form of an ointment, a cream, a milk,a pomade, a powder, an impregnated pad, a syndet, a wipe, a solution, agel, a spray, a mousse, a suspension, a lotion, a stick, a shampoo or awashing base. It may also be in the form of a suspension of microspheresor nanospheres or lipid or polymer vesicles or a polymer patch and ahydrogel allowing controlled release. This pharmaceutical compositionfor topical application may be in anhydrous form, in aqueous form or inthe form of an emulsion.

In one preferred variant of the invention, the pharmaceuticalcomposition for topical application is in the form of a solution, a gelor an emulsion.

Such pharmaceutical compositions may be manufactured according toprocesses that are well known to those skilled in the art.

Various examples of preparation and use of the compounds according tothe invention will now be given, for illustrative purposes and with nolimiting nature.

EXAMPLES Example 1 Synthesis of 2-(2-methyl-5-nitroimidazol-1-yl)ethyl(S)-2-(2-fluorobiphenyl-4-yl)propionate

To a solution of (S)-flurbiprofen (2 g, 8.17 mmol) and metronidazole(1.4 g, 8.17 mmol) in 30 mL of dichloromethane are successively added 50mg of DMAP (4-dimethylaminopyridine) and then 1.6 g (8.17 mmol) of EDC(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide). The reaction mixture isstirred for 4 hours at room temperature and then quenched with 50 mL ofwater and extracted with 50 mL of dichloromethane. The organic phase iswashed with 2×50 mL of 5% citric acid solution and then with 50 mL ofwater. The organic phase is dried over magnesium sulfate and thenevaporated under reduced pressure. The residue is dissolved in 10 mL ofisopropanol and then brought to reflux. After cooling to roomtemperature, the product crystallizes in the form of white crystals.

2.1 g of 2-(2-methyl-5-nitroimidazol-1-yl)ethyl(S)-2-(2-fluorobiphenyl-4-yl)propionate are obtained.

Yield=64%.

¹H NMR (CDCl₃): 7.95 (s, 1H); 7.55 (dd, 2H, J=1 Hz, J=7 Hz); 7.48 (t,2H, J=5 Hz); 7.41 (m, 2H); 7.05 (m, 2H); 4.60-4.44 (m, 4H); 3.69 (q, 1H,J=7 Hz); 2.31 (s, 3H); 1.51 (d, 3H, J=7 Hz).

¹³C NMR (CDCl₃): 173.4; 161.0; 158.5; 150.6; 140.9; 140.8; 135.2; 132.2;131.2; 131.2; 129.0; 128.5; 127.8; 123.4; 115.2; 115.0; 62.9; 45.1;44.9; 18.3; 13.9.

NB: In order to obtain the compound of formula (I) according to theinvention in racemic form, the process described above is used replacingthe S-flurbiprofen with racemic flurbiprofen.

Each enantiomer of the compound of formula (I) is identified by chiralHPLC under the following conditions:

Column IC 250 × 4.6 mm 5 μm Route A Heptane 75% Route B Isopropanol 25%Flow rate = 1.4 ml/min (S): 12.4 minutes/(R): 14.2 minutes

Example 2 Stabilities Evaluated on Keratinocyte Cultures

The stability on keratinocyte cultures is evaluated using human neonatalkeratinocytes (Cell'N Tech) cultured in a 75 cm² flask and detached at90-100% of confluence with vegetable trypsin (trypLE GIBCO). Thecompound of formula (I) was tested at 2 μM in the medium CNT-057 (Cell'NTech) supplemented with 0.1% pluronic acid in 24-well plates. The finalDMSO concentration is 0.1%. Degradation kinetics are performed with aTecan EVO robot over 24 hours. The samples taken are then assayed byLC/MS/MS (Micromass) in comparison with a calibration range of the testproduct, prepared under the same conditions as the samples (1/3 culturemedium and 2/3 methanol). The chromatographic conditions are optimizedfor each product. An assay of the appearance of metronidazole is alsoperformed using these same samples.

The half-life time (t_(1/2)) of 2-(2-methyl-5-nitroimidazol-1-yl)ethyl2-(2-fluorobiphenyl-4-yl)propionate is 6 hours.

That of its S enantiomer, namely 2-(2-methyl-5-nitroimidazol-1-yl)ethyl(S)-2-(2-fluorobiphenyl-4-yl)propionate, is 18 hours.

For comparative purposes, the metronidazole esters with indomethacin,niflumic acid, diflunisal or ketorolac do not become hydrolysed on thekeratinocyte cultures.

Example 3 Anti-Inflammatory Activity

a) Model of Acute Inflammation on Mouse Ear: Arachidonic Acid-InducedOedema

The anti-inflammatory activities of the compound of formula (I) inracemic form, of the S enantiomer of the compound of formula (I), ofmetronidazole and of flurbiprofen were measured in an in vivo testperformed on a mouse model. This model consists in inducing inflammationof the mouse ear with a single application of arachidonic acid (AA).Female Balb/c ByJlco mice are used. The oedema is induced by applying tothe mouse's ear 20 μL of AA dissolved to 4% in a 1/1 THF/methanolmixture. The anti-inflammatory activities of the S enantiomer of thecompound of formula (I), of the compound of formula (I) in racemic form,of metronidazole and of flurbiprofen were evaluated after topicalapplication onto the inner face of the mouse's ear of 20 μL of asolution of the compound in a 1/1 THF/methanol mixture containing 4% AA.

Solutions containing 0.01%; 0.03%; 0.1%; 0.3%; 1% and 2% of the testcompound are thus prepared. The percentages correspond to the weight ofthe test compound per volume of solution. The oedema is evaluated, 1hour after application, by measuring the thickness of the ear using anOditest® micrometer. The oedema induced by AA alone is evaluated, 1 hourafter application, by measuring the thickness of the ear using anOditest® micrometer. It is evaluated relative to a group comprising onlythe vehicle (1/1 THF/methanol).

The inhibition of the oedema is expressed as a percentage of reduction,by the test molecule and at the test concentration, of the oedemainduced by AA alone.

The IC₅₀ corresponds to the concentration (or dose) at which 50%inhibition of the oedema induced by AA alone is observed.

The results are as follows:

-   -   metronidazole has no anti-inflammatory activity in this model;    -   flurbiprofen (racemic) has an IC₅₀ of 0.037%. At a dose of 0.1%,        it inhibits 60% of the oedema induced by AA alone.    -   the racemic compound of formula (I), namely        2-(2-methyl-5-nitroimidazol-1-yl)ethyl        2-(2-fluorobiphenyl-4-yl)propionate, has, at a dose of 1%,        anti-inflammatory activity equivalent to that of flurbiprofen        (racemic) at the 0.1% dose presented above.    -   the S enantiomer of the compound of formula (I), namely        2-(2-methyl-5-nitroimidazol-1-yl)ethyl        (S)-2-(2-fluorobiphenyl-4-yl)propionate, has an IC₅₀ of 1%.

At a dose of 1%, it inhibits 50% of the oedema induced by AA alone.

These results show that at a dose of 1%, the racemic compound of formula(I), namely 2-(2-methyl-5-nitroimidazol-1-yl)ethyl2-(2-fluorobiphenyl-4-yl)propionate, or its S enantiomer, namely2-(2-methyl-5-nitroimidazol-1-yl)ethyl(S)-2-(2-fluorobiphenyl-4-yl)propionate, inhibits at least 50% of theoedema induced by AA in this model of anti-inflammatory activity.

b) Model of acute inflammation on mouse ear: oedema induced by TPA(phorbol 12-myristate-13-acetate)

The anti-inflammatory activities of the compound of formula (I) inracemic form, of metronidazole and of flurbiprofen (racemic) weremeasured in an in vivo test performed on a mouse model.

The model used is the model of mouse ear inflammation induced by asingle application of TPA (phorbol 12-myristate-13-acetate). FemaleBalb/c ByJlco mice are used.

The oedema is induced by applying to the ear 20 μl of 0.01% TPAdissolved in ethanol.

The racemic compound of formula (I) is dissolved, at the desiredconcentration, in the 0.01% TPA solution and thus applied to a group ofmice at the same time as the TPA.

Similarly, flurbiprofen (racemic) is dissolved, at the desiredconcentration, in the 0.01% TPA solution and thus applied to anothergroup of mice at the same time as the TPA.

Finally, metronidazole is dissolved, at the desired concentration, inthe 0.01% TPA solution and thus applied to another group of mice at thesame time as the TPA.

The oedema is evaluated, 6 hours after application, by measuring thethickness of the ear using an Oditest® micrometer.

The TPA-induced oedema is evaluated relative to the ethanol vehiclegroup. The inhibition, with the racemic compound of formula (I), withflurbiprofen (racemic) or with metronidazole, of the oedema induced byTPA alone is expressed by the IC₅₀.

The IC₅₀ corresponds to the concentration (or dose) at which 50%inhibition of the oedema induced by TPA alone is observed.

The results are as follows:

metronidazole has no anti-inflammatory activity in this model;

flurbiprofen (racemic) has an IC₅₀ of 0.22%.

The compound of formula (I) in racemic form, namely2-(2-methyl-5-nitroimidazol-1-yl)ethyl2-(2-fluorobiphenyl-4-yl)propionate, itself has the same IC₅₀ asflurbiprofen (racemic), i.e. equal to 0.22%.

This compound thus has noteworthy anti-inflammatory activity.

Example 4 Penetration in Rats

The compound of formula (I), an enantiomer thereof or a pharmaceuticallyacceptable salt thereof is applied to the skin of Wistar SD rats.

In parallel, an equimolar mixture of metronidazole and flurbiprofencorresponding to the same dose is applied for comparative purposes.

The lateral and dorsal hairs of each of the animals are close-cropped,approximately 24 hours before the single application. The applied volumeis 10 microlitres/cm² over an area of 41 cm² (5.5×7.5 cm²).

The vehicle used is composed of propylene glycol/ethanol/water/Tween 80in respective weight proportions of 30/44/25/1. Skin and blood samplesare collected at 45 minutes, 1 hour 30 minutes, 2 hours 30 minutes, 4hours, 6 hours, 8 hours, 16 hours and 24 hours on three animals pergroup. The plasmas are prepared by precipitation in a 2/1acetonitrile/methanol mixture and the biopsies are crushed using acryomill system and then analysed by LC/MS/MS.

By way of example, a solution of 1.4%2-(2-methyl-5-nitroimidazol-1-yl)ethyl(S)-2-(2-fluorobiphenyl-4-yl)propionate is applied.

In parallel, a solution containing 0.6% metronidazole and 0.9%flurbiprofen is applied.

The amount of metronidazole detected in the plasma is about 2.3 timessmaller when the 1.4% 2-(2-methyl-5-nitroimidazol-1-yl)ethyl(S)-2-(2-fluorobiphenyl-4-yl)propionate solution is applied, and that offlurbiprofen about 6.7 times smaller in comparison with the applicationof a solution containing 0.6% metronidazole and 0.9% flurbiprofen.

1. A compound of formula (I) below:

or an enantiomer or pharmaceutically acceptable salt thereof.
 2. Thecompound as defined in claim 1, wherein the compound is incorporatedinto a medicament.
 3. The compound as defined in claim 1, wherein thecompound is effective in treating rosacea.
 4. The compound as defined inclaim 1, wherein the compound is effective in treating an inflammatorypathology.
 5. The compound as defined in claim 1, wherein the salt ofthe compound of formula (I) or of an enantiomer thereof is a salt of thecompound or an enantiomer thereof with a pharmaceutically acceptableacid.
 6. The compound as defined in claim 1, wherein thepharmaceutically acceptable acid is selected from the group consistingof: a) a pharmaceutically acceptable inorganic acid; and b) apharmaceutically acceptable organic acid.
 7. The compound as defined inclaim 1, wherein the compound is selected from the group consisting of acompound of formula (I), a hydrochloride of the compound of formula (I),a citrate of the compound of formula (I), a salicylate of the compoundof formula (I), a benzoate of the compound of formula (I), and an Senantiomer of any one of these compounds.
 8. The compound as defined inclaim 1, wherein the compound is 2-(2-methyl-5-nitroimidazol-1-yl)ethyl(S)-2-(2-fluorobiphenyl-4-yl)propionate.
 9. A pharmaceutical compositionfor topical application comprising a compound as defined in claim 1 anda pharmaceutical carrier.
 10. The composition as defined in claim 9,said composition being in the form of a solution, a gel or an emulsion.11. The composition as defined in claim 9, wherein the compound ispresent in an amount of 0.001% to 10% by weight relative to the totalweight of the composition.
 12. The compound as defined in claim 6,wherein the pharmaceutically acceptable inorganic acid is selected fromthe group consisting of hydrochloric acid, sulfuric acid, phosphoricacid, nitric acid, and hydrobromic acid.
 13. The compound as defined inclaim 6, wherein the pharmaceutically acceptable organic acid isselected from the group consisting of acetic acid, tartaric acid, maleicacid, hydroxymaleic acid, fumaric acid, citric acid, lactic acid, mucicacid, gluconic acid, benzoic acid, succinic acid, oxalic acid,phenylacetic acid, methanesulfonic acid, toluenesulfonic acid,benzenesulfonic acid, salicylic acid, sulfanilic acid, aspartic acid,glutamic acid and ascorbic acid.